ABSTRACT Aging is associated with dramatic alterations in immune function, resulting in reduced immunologic responsiveness and increased mortality from infections. The underlying mechanisms remain poorly understood, however. Currently, most information is derived from studies using peripheral blood, which contains approximately only 2% of total body lymphocytes (the key effectors of adaptive immunity). This compartment demonstrates a profound age-associated alteration in function and composition of the memory CD8+ T lymphocyte pool that is due, in large part, to the increasingly disproportionate accumulation of blood immune cells with features of replicative senescence. These are defined as cells with short telomeres, inability to proliferate and associated phenotypic changes. There are no reliable data on the age-related changes in T lymphocytes in the human gastrointestinal tract, which is the major reservoir of total body lymphocytes and an anatomical region of high antigenic exposure. However, our preliminary studies on a cohort of young individuals document significant differences in T cell phenotypes between the gut and blood from the same individual. The overarching goal of the proposed studies is to determine the effect of aging on gut-associated lymphoid tissue (GALT) and to analyze the impact of chronic antigenic stimulation on these changes. Based on data suggesting that CD8+ T lymphocyte aging is largely driven by chronic viral infections, such as cytomegalovirus, we will assess the impact of chronic antigenic stimulation by also including persons infected with the human immunodeficiency virus. This treatable chronic viral infection allows us to test whether lowering the antigenic burden, via direct viral suppression, retards the age-related accumulation of senescent cells in the gut by reducing the impact of the chronic viral infection. Aim 1a will compare phenotypic and functional parameters of gut and blood samples from healthy young (20-35 yrs) and older (50-65 yrs) individuals. Aim 1b will determine the additive impact of vigorous persistent antigenic stimulation on the normative age-related changes in the CD8+ T lymphocyte compartments within blood and gastrointestinal mucosa of individuals in the same age groups, and Aim 2 will evaluate whether the altered GALT rate of senescent CD8+ T lymphocyte accumulation is retarded by treatment that reduces the viral load, and thus the level of chronic antigenic stimulation. The proposed research, will, therefore provide the first comprehensive analysis of age-associated changes in the human gut, the largest lymphoid organ in the body. The results will have significant clinical implications in terms of age- appropriate treatments and vaccine development for the ever-increasing older U.S. population.